We will use structural biology tools to investigate DNA-processing enzymes from human pathogens, and those relevant to genome integrity or disease process. An area of particular interest is the mechanism of retrovirus integration by the viral integrase (IN), which forms a multimeric complex with both ends of the linear viral DNA genome and captures a cellular target DNA for concerted insertions of the viral DNA termini. The IN-viral DNA complex formed by HIV-1 IN is the target of a class of antiviral drugs called IN strand-transfer inhibitors. Therefore, a better understanding of the IN-DNA interactions is important for improving the clinically used IN inhibitors as well as designing next-generation inhibitors. We are pursuing crystal structures of IN-DNA complexes from HIV-1 and closely related retroviruses, and structure of those in complex with the host co- factor LEDGF/p75. Our preliminary data suggest that the architectures of the multimeric IN complex containing viral and target DNA molecules are distinct between the extensively characterized prototype foamy virus and other retroviruses with smaller 3-domain INs, including Rous sarcoma virus and HIV-1. Besides retrovirus INs, we are interested in the bacterial and pox viral enzymes responsible for regenerating the hairpin telomeres of linear chromosomes by resolving concatemeric replication intermediates. We also study enzymes involved in cleaning damaged DNA ends for error-free repair by end-joining. Through studies of these systems, we intend to learn novel principles in DNA-protein interactions and obtain structural information that can aid in inhibitor development or design of useful engineered enzymes.